The 5-year survival rate for patients with oral squamous cell carcinoma (SCC), at 40%, is among the worst of all sites in the body and has not improved over the past 40 years. Improved understanding of the molecular basis of oral SCC progression and tumorigenesis can contribute to development of novel strategies for diagnosis, cancer risk assessment and classification, as well as targeted therapies for prevention and treatment. Genomic analysis is of particular utility, since it is generally accepted that oral SCC develop via accumulation of genetic and epigenetic changes in a multi-step process. Recent work in our laboratory found that oral squamous cell carcinoma genomes are characterized by recurrent copy number changes, including recurrent narrow amplicons spanning <3 Mb (1). These amplicons focus attention on the genes they encompass as candidate oncogenes that contribute to oral cancer development. Moreover, a number of these amplicons have also been observed in oral epithelial dysplasia, a pre-malignant condition which frequently precedes cancer development. Thus, in this particular tumor type, it appears that amplicons signal genes important for the development of this disease. Here we will focus on further analysis of three candidate oncogenes implicated in oral cancer because they, or members of their genetic network, mapped to a narrow amplicon in oral SCC. We will investigate when and where these genes are expressed during disease progression (Aim 1). In Aim 2, we will investigate how, i.e. by what mechanism, they contribute to cancer development (e.g. alterations in growth and differentiation of the squamous epithelium, metastasis, etc.). In addition, we will evaluate the capability of genomic aberrations detected by array CGH to predict progression of pre-malignant lesions to cancer. The 5-year survival rate for patients with oral squamous cell carcinoma is 40%, among the worst of all sites in the body. The most fundamental way to make progress toward improving diagnosis and treatment of oral cancer is to elucidate the specific genes and the interactions among genes that become abnormal as cancer develops.